It is generally desirable to provide pharmaceuticals in a tamper-resistant form to maximise the chance that they are taken in the manner intended. This, in turn, ensures that the pharmaceutical is likely to have the full pharmacological effect desired. Even more significantly, the provision of pharmaceuticals in a tamper resistant form means that they are more difficult to abuse.
Pharmaceuticals comprising certain types of drugs are of course more likely to be targeted for abuse than others. For example, dosage forms (e.g. tablets) containing an opioid agonist, a tranquilizer, a CNS depressant, a CNS stimulant or a sedative hypnotic are frequently the targets of abuse, especially dosage forms containing an opioid agonist.
Opioid analgesics are important pharmaceuticals for the treatment and management of pain. Abusers generally aim to modify dosage forms containing opioid analgesics, particularly controlled-release dosage forms, and then administer them in such a way that a high in vivo concentration is achieved over a short period of time so as to experience a euphorogenic effect. Opioid-containing controlled-release tablets may, for example, be crushed in order to make the opioid present therein available for immediate release upon oral or nasal administration. Another form of abuse that occurs is the extraction of opioid from opioid-containing formulations mainly by using ethanol although other solvents, e.g. water or acetone, are also used. The resulting solution may then be crudely administered by injection. Additionally, abusers sometimes disregard the instructions for use of opioid-containing dosage forms and concomitantly imbibe alcohol when taking the dosage form to enhance drug release. This may result in an abuser receiving a dose of opioid more rapidly than intended.
To minimise the possibility that abuse occurs, it has been proposed to formulate opioid analgesics into tablets with high molecular weight polyethylene oxide (PEO). The PEO would serve to control the rate of release of opioid from the dosage form and to impart crush resistance to it. The PEO would also ensure that, if the dosage form is subjected to ethanol extraction, a viscous solution would result that is resistant to syringing and injection.
The amount of PEO, and in particular its ratio to drug and other excipients (if present) in the dosage form, that is necessary to achieve control of release rate and crush resistance is, however, limiting. In particular, it is difficult to prepare high strength dosage forms (i.e. dosage forms containing relatively high amounts of drug) as the amount of PEO required to control the release rate of the drug therefrom and provide crush resistance is impractically high. The dosage form (e.g. tablet) becomes too large and heavy for easy administration. As a result, it is difficult to provide extended-release dosage forms, especially those releasing drug over 24 hours, that are also tamper resistant.
Melt extruded multiparticulates comprising opioid analgesics are also known. These are described, for example, in WO2005/079760. Some of the polymers present in such multiparticulates to facilitate melt extrusion may confer upon the multiparticulates a certain level of crush resistance. Indeed it is known that the higher the level of such polymers present in such multiparticulates the more resilient they are to crushing.
On the other hand, however, the above-described multiparticulates are still somewhat susceptible to abuse by alcohol extraction. It is known, for example, that these multiparticulates release 2 to 3 times more opioid in the presence of alcohol than in its absence. It is thought that this is caused by drug release occurring from the surfaces created by cutting the melt extrudate during the pelletisation process to produce multiparticulates. This is, however, highly undesirable when the likelihood of abuse is relatively high.
Accordingly, there is a need for alternative dosage forms and especially for tamper resistant dosage forms that possess crush resistance as well as resistance to solvent (e.g. ethanol) extraction. The dosage form should advantageously be of a shape, size and weight that can be taken orally with ease. Of course, the dosage form should also be easy to make in a cost effective manner.
It has now been surprisingly found that if melt-extruded particulates comprising a drug are incorporated into a matrix and the mixture is formed into a dosage form (e.g. a tablet), the dosage form possesses excellent alcohol-extraction resistance properties (i.e. tamper resistance) as well as crush resistance. The matrix in which the particulates are present provides resistance to alcohol extraction by forming a gel or viscous solution on exposure to alcohol that resists syringing or injection. The composition and size of the particulates comprising drug provide crush resistance thus even if the matrix is a crushable material, all that can be obtained are the particulates that are difficult to separate and too small to easily crush further but too large for nasal administration. The matrix may also comprise a curable polymer and, in this case, the matrix advantageously provides the overall dosage form with crush resistance.